Disruptions in protein homeostasis (proteostasis) have long been implicated as a mechanism that leads to neurodegeneration, however global changes that occur to the proteome have not been explored in human midbrain neurons. a-Synuclein, the protein that accumulates within defining histopathological inclusions called Lewy bodies, disrupts essential cellular pathways linked to proteostasis such as protein trafficking and lysosomal degradation pathways. Our previous studies using familial PD neuronal cultures harboring a triplication in the a-syn gene (SNCA trp) indicates that lysosomal proteolysis and protein trafficking are disrupted. Here, we propose to study the downstream consequence of a-syn accumulation and its global effects on the proteome using induced pluripotent stem cell (iPSC)-derived human midbrain models and PD brain. We hypothesize that a-syn accumulation leads to a selective accumulation and aggregation of a metastable sub-proteome with essential cellular functions. Aggregation of these critical proteins leads to loss-of-function and subsequent neurodegeneration. These studies are exploratory and we anticipate will generate new hypotheses for how human neurons handle the burden of protein accumulation in disease. They may contribute to our understanding of how a-syn accumulation leads to neurodegeneration, and identify novel pathways for therapeutic intervention. From a basic science perspective, these studies will help us to understand how human neurons respond to aggregation-induced stress through remodeling of the proteome.